The central hypothesis of this proposal is that neuronal death (reflected primarily by gray matter volume loss) resulting from demyelination and inflammation-induced axonotomy (rather than myelin loss per se) is the primary factor in induction and progression of physical and neurocognitive disability in patients with multiple sclerosis (MS). We will detect and measure neuronal loss in our well- characterized cohort of MS patients over a 5 year period using magnetic resonance imaging and proton magnetic resonance spectroscopy (1H MRS). In Specific Aim 1 MS lesions will be assessed by measuring T2 and T1- enhanced lesion volumes and magnetization transfer ratio histogram parameters (MTRHP) in patients with relapsing-remitting and secondary progressive disease. This data will be correlated with total brain parenchymal volume and will be used to characterize the effect of MS lesion on the gray and white matter volumetric components of brain parenchyma. The brain volumetric measurements will be compared to clinical measures of disability including Kurtzke Expanded Disability Status Scale (EDSS) and a specific battery of neuropsychological tests. Specific Aim 2 includes quantitation of N-acetylaspartate over the whole brain (WBNAA), a reproducible measure of viable neuron number based upon 1H MRS, and comparison of the results to age-matched controls over a duration of 5 years. Specific Aim 3 is to examine the correlations between the volumetric and clinical measurements in Specific Aim 1 and WBNAA in Specific Aim 2. The techniques that we have developed and validated, which include computerized quantitation of brain parenchyma and the gray and white matter components of parenchyma, analysis of the MTR histogram, and measurement of WBNAA will be utilized to estimate neuronal loss. Additionally we will determine the course of neuronal change over a 5 year duration, and will correlate the markers of neuronal loss with clinical measures of disability. This approach will, for the first time, provide important new data on the full extent of neuronal loss in patients with MS. We feel that these studies will ultimately lead to a more thorough understanding of the natural history of neurodegeneration in MS, and to a more rational design of outcome measures, and patient stratification in MS treatment trials. In addition, these studies will provide a basis for analysis of both primary and secondary central nervous system (CNS) neurodegeneration in other common and devastating disorders such as AIDS dementia complex, Alzheimer's disease and traumatic brain injury.